Genetic dissection of cell type-specific congenital heart disease variants reveals ETS1 control of vascular smooth muscle cell fate.

A single-cell multiomic atlas of human cardiac differentiation prioritized 610 CHD-associated noncoding variants in lineage- and chromatin-state-specific regulatory elements, including repressed and bivalent regions.

• Why it matters: Many CHD risk variants sit in cis-regulatory DNA, but how variants in repressed or bivalent chromatin affect cell type-specific heart development remains unclear.
• What they did: The study profiled H3K27ac, H3K27me3, H3K4me3, and transcriptomes in individual differentiating human cardiac cells, then used CRISPR knockin to test selected variants and map their effects.
• The result: A Polycomb-marked variant near ETS1 caused local H3K27me3 loss, H3K27ac gain, and ETS1 up-regulation, redirecting differentiation toward migratory ETS1+ vascular smooth muscle cells.

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